Measuring remission in depression



b y J . D . G u e l f i , F r a n c e

Julien Daniel GUELFI, MD
Université Paris Descartes
Clinique des Maladies Mentales et de l’Encéphale (CMME)
Chef de Service: Pr F. Rouillon
Hôpital Sainte-Anne
Paris, FRANCE

Depression tends to be recurrent, presenting as a chronic rather than as a truly episodic condition, at least in most cases: 71% of patients remain symptomatic 1 year after diagnosis,1 and fewer than half are fully symptom-free 2 years after the index episode.2 Although the concept of remission has come under much recent scrutiny, there is still no consensus definition. In the last 15 years, attention has focused increasingly on the quality of recovery from an index episode, given that outcome in patients with residual symptoms is distinctly less favorable than in patients who are symptom- free. The present paper reviews recent developments in the concept of remission, before discussing the various methods proposed for its assessment and the clinical implications of the variable nature of residual symptoms. In a longitudinal study whose main results appeared in 2004, Kennedy et al3,4 showed that patients were only symptom-free for approximately half the mean 10-year follow-up; bouts of full depression occurred in 13% of follow-up months, bouts of minor depression in 15% of months, and bouts with residual symptoms in 20%. There is also evidence that the accumulation of recurrent depressive episodes aggravates the disease.2 Episode duration varies, becoming increasingly longer in some reports, but shorter in others.5 Long-term studies suggest that duration—whether symptom-free,6 with moderate symptoms, or full depression—is one of the most valuable criteria in patient assessment.

Remission, residual symptoms, and relapse

Several studies since the early 1990s have established that residual symptoms are common in treated depression, even in patients judged to be in remission. The most conclusive evidence, following a variety of preliminary studies,7-11 came from Paykel et al in 199512 and Judd et al in 1998 and 2000.1,13 Over 20% of patients retain clinically significant symptoms 1 year after depression.14 These percentages are much higher in the elderly.15,16
The presence of such symptoms is also a major predictor of early relapse. In 1992, Thase et al17 showed in 48 depressed patients receiving cognitive behavioral therapy (CBT) that the risk of relapse or recurrence in the year following the episode was much lower in full than in partial responders (9% vs 52%). Three years later, Paykel et al confirmed that symptom-free patients (n=40) had a much lower risk of early relapse (25%) than those with residual symptoms (n=17; 76%) (Figure 1).12
In their 10-year follow-up study, Judd et al1 found a mean time to relapse of 231 weeks in symptomfree patients, compared with 68 weeks in those with residual symptoms. The difference was even more striking when taking into account not just major depressive disorder but all types of depression (minor, acute, and chronic [dysthymia]): 184 versus 33 weeks. Review of major depressive episodes showed that symptom-free patients had a risk of relapse that was less than one-third that of patients with residual symptoms. A 2008 review by Möller18 cites two other studies highlighting the increased risk associated with residual symptoms: Lin et al in 199819 and Pintor et al in 2003,20 who found relapse risks of 15.2% versus 67.6% over 2 years.

Remission, generally defined as the disappearance of the diagnostic criteria of depression for at least 2 consecutive months, has gradually ousted treatment response as the gold-standard end point for evaluating antidepressant efficacy in long-term controlled trials. Partial remission, defined as the persistence of residual symptoms, is a risk factor for early relapse and subsequent recurrence; it is a heterogeneous state, in which the persistence of even mild symptoms reduces the hope of full functional recovery. The best criteria of high-quality remission are the disappearance of the diagnostic criteria of depression for _2 months, a score of 1 on the Clinical Global Impression–Improvement scale, a score _3 on the Hamilton Rating Scale for Depression, and a return to premorbid general functional status. Careful evaluation of residual symptoms informs the choice of the most appropriate therapeutic strategy for achieving full remission.
Medicographia.
2009;31:192-197. (see French abstract on page 197)

Keywords: depression; questionnaire; rating scale; remission; residual symptom

Definitions and criteria

In 1989 the MacArthur Foundation Research Network convened a task force to establish operational criteria for the terms treatment response, remission, relapse, and recurrence. Its first publications, in particular by Ellen Frank, Robert Prien, David Kupfer, and others, were based on the review of 121 papers published in 1987-1988 in nine English-language journals. Their work differentiated the conventional efficacy measure, treatment response, from remission. Response had generally signified a 50% reduction in overall score on a validated depression scale. This end point gradually gave way to the remission end point following such studies as those by Bakish in 2001,21 Nierenberg and DeCecco the same year,22 Thase in 2003,11 and Cuffel et al23 and Keller24 in 2004. Lecrubier reviewed the widely differing definitions of remission in 2002.25
In addition to presence/absence of symptoms, duration is a key criterion. The diagnostic criteria of depression must disappear for _8 consecutive weeks before a depressive syndrome can be considered to have resolved. Until that time, the depression can be considered as being in remission to a degree, dependent on the persistence of certain symptoms, provided these are insufficient in number and intensity to warrant rediagnosis as depression. In 1994, the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) officialized the terminology of total and partial remission: “Full remission requires a period of at least 2 months in which there are no significant symptoms of depression. There are two ways for the episode to be in partial remission: (i) some symptoms of a major depressive episode are still present, but full criteria are no longer met; or (ii) there are no longer any significant symptoms of a major depressive episode but the period of remission has been less than 2 months.”
The American College of Neuropsychopharmacology Task Force adopted the following position. Remission came to be defined as the disappearance for at least 2 to 3 consecutive weeks of the main symptoms of depression (depressed mood, with loss of interest and pleasure) and the total or near dis- appearance of the nine DSM-IV diagnostic criteria of major depression. If these conditions remain stable for 4 months, remission becomes resolution.
Opting for strict criteria facilitated recognition of high-quality remission. In some cases it also revealed one antidepressant as more effective than another after comparison in terms of treatment response had failed to separate the two drugs. Thus Ferrier in 199926 combined the disappearance of the diagnostic criteria of depression and a Clinical Global Impression–Improvement (CGI-I) score of 1 to show that the serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine was more effective than selective serotonin reuptake inhibitors (SSRIs).

Figure 1
Figure 1. Proportion of patients with ( ) and without ( ) residual symptoms relapsing after remission from depression.

After reference 12: Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barocka A. Residual symptoms after partial remission: an important outcome in depression. Psychol Med. 1995;25: 1171-1180. Copyright © 1995, Cambridge University Press.

Symptom-measuring tools

Diagnostic criteria
A clear distinction needs to be drawn between diagnostic criteria and rating scales or questionnaires. The purpose of diagnostic criteria is to confirm the presence or absence of a diagnosis, usually after completing a semi-structured or structured interview. DSM-IV criteria are the most commonly used, in combination with the Structured Clinical Interview for DSM-IV (SCID).27 This tool is used to confirm the absence of an ongoing depressive syndrome and to identify any residual symptoms. Kupfer published specific criteria for the elderly in 2005,28 and Kennard et al described application of the criteria to adolescents in 2006.29

Rating scales
Rating scales are normally used to measure symptom intensity. The Hamilton Rating Scale for Depression (HAM-D)30 remains the world’s most widely used depression scale and the subject of a still-extensive literature, not all of which is favorable. The 2004 broadside from Bagby et al31 accused it of being psychometrically and conceptually flawed, and highlighted such shortcomings as poor inter-rater and retest reliability, and poor replication of the multidimensional factor structure. However, the consensitivity of HAM-D to change has been rarely questioned. Until recently, the scientific community more or less generally accepted the 1991 proposal by the MacArthur Foundation Task Force32 to define full remission as a maximum total score of 7 on the 17-item HAM-D (HAM-D17) and partial remission as a score of 7 to 13. This is no longer the case today. Zimmerman et al33 provided convincing evidence of heterogeneity in ex-depressive populations with average total scores <7, where the risk of relapse in particular was higher at scores of 6 or 7 than at 2 or 3. Nor do all symptoms carry equal weight. Anxiety, somatic concerns, and sleep disturbance are much less specific than loss of interest or anhedonia. Zimmerman et al also showed less psychosocial impairment in patients with a total HAMD17 score _2 than in those with a score of 3 to 7.33 Certain investigators34 continue to defend the use of HAM-D, especially when concentrated into more homogeneous subscales: 7-item scales have proved sensitive to change,35,36 with a score of 3 on HAM-D7 being equivalent to 7 on HAM-D17. Even a 6-item subscale has proved both sensitive to change and highly homogeneous.37 The Montgomery–Åsberg Depression Rating Scale (MADRS)38 has attracted similar criticism, having been found to be sensitive to change but with an unstable factor structure. Nor does a low final score (<10) guarantee remission in the absence of the duration criterion. The Inventory of Depressive Symptomatology (IDS) was developed from 1986 onward,39 with the main validation study being published 10 years later. 40 A 16-item short form was produced in 2003,41 with further publications in 200642,43 comparing clinician and patient ratings. Our own (unpublished) studies with E. Corruble showed that the sensitivity to change of the self-rated questionnaire did not exceed that of its clinician-rated counterpart. Depression questionnaires have yet to prove more sensitive to change than HAM-D, even if the Beck Depression Inventory (BDI)44 has been used to assess change primarily via its cognitive variables. However, this relative overall insensitivity does not disqualify questionnaires from being used to assess change in depressed patients. Residual symptoms are sufficiently varied to justify a palette of therapeutic measures and sophisticated symptom analysis, without forgetting the physical symptoms45 that must always be taken into account before deciding treatment. Specialized questionnaires can also often be useful in association with certain psychotherapy techniques. In a quarter of depressed outpatients, there is discordance between self-reported symptom severity and psychosocial functioning ratings46 that must also enter into assessment, especially in patients who deny concurrent psychosocial impairment. Thus the quality of functional remission must also be assessed.

Evaluating functional remission

Several investigators have emphasized the importance of functional remission in conjunction with a return to premorbid cognitive function. This type of assessment is based in part on tools designed to evaluate social and occupational integration, executive functions, well-being, or more generally, quality of life. Thus Zimmerman et al46,47 showed that the three items most frequently judged to be critical in determining remission were the presence of features of positive mental health such as optimism and self-confidence, a return to one’s normal self, and a return to usual level of functioning.
One of the best questions to ask ex-depressives is whether they feel back to their pre-depression normal self in terms of general functioning. Indeed the return to normal activity and premorbid functioning is now considered the main treatment objective. When general functioning remains impaired and there is a suggestion of personality disorder, assessment of the relationship between residual symptoms and personality becomes particularly important. The tools most frequently used for this purpose are the SCID or similar instruments for assessing personality according to the DSM-IV classification, such as the Structured Interview for DSM-IV Personality (SIDP-IV)48 or the Personality Assessment Schedule49 favored by Gene Paykel’s group in Cambridge UK.12,50,51
Assessment of full remission is ultimately a simple matter, involving confirmation of the lasting disappearance of depressive symptoms and the return to previous functioning (complete with the date of the anticipated return to work, as applicable).
Functional remission in the presence of persistent residual symptoms is a trickier problem, requiring psychometric screening to pinpoint the residual symptoms concerned, given that these vary in their functional impact. The 2-year study in 219 depressives with psychotic characteristics published by Tohen et al52 in 2000 is a case in point. Alongside conventional syndromal recovery, Tohen et al used the concept of functional recovery defined by the return to patients’ former vocational and residential status. Time to this result was shortest in bipolar married patients aged _30 years with no comorbidity, treated from disease outset, and hospitalized only briefly. In this study, functional recovery proved 2.5-fold less frequent than symptomatic recovery. Alongside specialized tools such as the Modified Vocational Status Index and Modified Vocation Code Index, the main end point was simply a CGI-I score of 1 to 2 for at least 8 weeks.
This recent transformation in the primary end point of randomized controlled trials with antidepressants inevitably results in studies that are longer than the classic efficacy trials with improvement as the primary end point.11,26 Thus whereas after treatment for 12 weeks the majority of patients have improved and are therefore considered as responders, the percentage of those in remission generally remains around 30%.45 Longer follow-up is mandatory in order to confirm the stability and quality of the remission achieved. Specific tools have been proposed for this purpose such as the Longitudinal Interview Follow-up Evaluation (LIFE) published by Keller et al in 1987.53
Considerable effort is still needed to improve antidepressant compliance. Most randomized consensitivity trolled trials reach over-optimistic conclusions in so far as the patients they include tend to be young, in good physical health, with little comorbidity, and no major risk of suicide. In real life, however, half the patients prescribed an antidepressant stop taking it within the first month, and only one quarter continue treatment for more than 3 months.18,54 Hence the importance of assessing compliance during treatment and making the requisite effort to improve it as appropriate.

Residual symptoms and assessment of treatment indications

Boulenger’s 2004 review55 of residual symptoms emphasized the heterogeneity among patients in partial remission. In most cases some depressive symptoms persist; in other cases, symptoms predate the depressive syndrome. They typically include anxiety, substance abuse,23 and somatic concerns that may also herald relapse or recurrence. Many symptoms are in fact antidepressant side effects, in particular sleep disturbance,45,56 cognitive impairment, and various somatic (notably sexual) complaints, all of which are often long-term in nature,57 although in a study performed by Nierenberg et al in 1999,58 insomnia and fatigue appeared to persist after treatment (Figure 2).59
In the general population residual impairment in occupational functioning or other activities often resolves more rapidly than residual symptoms.14 Also, a higher level of symptom variability during maintenance treatment carries a higher risk of recurrence, 60 with personality playing a role in the frequency of symptom episodes.
Awareness of the importance of remission inspired a number of studies specifically designed to treat residual symptoms, whether with drugs, psychological approaches using information and psychoeducation, or CBT.9,22,43,56,59,61-67 Some emphasized the importance of cotreatments to control anxiety, sleep disturbance, drowsiness, apathy, and cognitive impairment.22,59 These included the use of various agents, including psychostimulants to enhance antidepressant efficacy or diminish side effects.67 The drawback to this type of approach, for which patients often plead on a drug per symptom basis, is that it results in multiple cotreatments that only compound the risk of side effects.
Results in the CBT literature are a mixed bag. In some cases, CBT provides no added benefit over an increase in antidepressant dose66; in other hands, it has positive effects.61-63,65,68-70 (reviewed in Perlis et al66). Its efficacy may be due to the fact, according to the Cambridge UK group, that it “changes the way that [patients] process depression-related material rather than changing belief or depressive thought content.”65 This multicenter controlled trial used classic rating tools supplemented by a number of questionnaires developed by specialists in the cognitive approach: (i) Peterson et al’s 1982 Attributional Style Questionnaire (ASQ),71 comprising three 7-point scales; (ii) Weissman and Beck’s 1978 Dysfunctional Attitudes Scale (DAS),72 comprising 40 7-point statements; (iii) Perceived Uncontrollability of Depression (UNCONTROL),65 a 10-item ad hoc scale; (iv) Characterological Self Blame for Depression (BLAME),65 a 7-point 10-item ad hoc scale; and (v) Metacognitive Awareness Questionnaire (MAQ),65 a 7-point 9-item instrument.

Figure 2
Figure 2. Frequency of residual major depressive disorder symptoms in responders (215 patients with major depressive disorder received a fixed dose of fluoxetine 20 mg for 8 weeks).

After reference 59: Fava M. Pharmacological approaches to the treatment of residual symptoms. J Psychopharmacol. 2006;20:29-34. Copyright © 2006, British Association for Psychopharmacology.

Analysis of patient responses revealed that “extreme responses (‘totally agree’ or ‘totally disagree’) to depression-related questionnaire items are the ‘tip of the iceberg’ reflecting underlying activity of mood-dependent, developmentally early, depressogenic schematic processing, uncorrected by subsequent reappraisal. Such schematic processing, it is suggested, is an integral part of self-perpetuating patterns of negative thinking.”65 The positive effects of therapy appear more probably due to the acquisition of compensatory skills than to changes in thought content.

Adolescents

Kennard et al29 treated 439 depressed adolescents with fluoxetine, CBT, a combination of the two, or placebo with clinical management (combination therapy proved significantly the most effective). The two main instruments were the Children’s Depression Rating Scale–Revised (CDRS-R) by Poznanski and Mokros,73 comprising 17 items scored from 1 to 5 or from 1 to 7, and Shaffer et al’s Children’s Global Assessment Scale (CGAS).74
In this study, the end point of a CDRS-R score <28 proved stricter than the disappearance of the diagnostic criteria of depression on Kaufman et al’s Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version (Kiddie-SADS-P/L).75

Conclusion

Assessment of remission quality in depression needs to combine semistructured interviews to determine the degree of disappearance of the diagnostic criteria of depression, specialized scales to assess the extent of residual symptoms, duration criteria, and questionnaires that target subjective mood as well as more objective end points of return to the normal functional self, return to work and normal social activities, and quality of life. Evaluation of associated symptoms, such as anxiety, substance abuse, or personality vulnerability, often provides a valuable guide to treatment. _

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FRENCH-LANGUAGE LITERATURE
A selection of recent publications in French devoted wholly or in part to the determinants of outcome in depression:
– Guelfi JD, Corruble E, Duret C, Pham-Scottez A, Purper-Ouakil D. Personnalité et Troubles de l’Humeur. Paris, France: Doin; 1999.
– Guelfi JD, Rouillon F. Psychiatrie. Paris, France: Elsevier-Masson; 2007.
– Hardy-Bayle MC, Olivier V. Quels Critères de Guérison Pour les Etats Dépressifs? Paris, France: Doin; 1998.
– Loas G, Chaperot C, Kapsambelis V, Legrand A. L’Anhédonie. L’Insensibilité au Plaisir. Paris, France: Doin; 2002.
– Olié JP, Poirier MF, Lôo H. Les Maladies Dépressives. 2nd ed. Paris, France: Médecine-Sciences Flammarion; 2003.
– Passerieux C, Hardy-Bayle MC. La Guérison des Etats Dépressifs. Paris, France: Doin; 2004.
– Rouillon F. Les Troubles Dépressifs Récurrents. Paris, France: John Libbey Eurotext; 2003.

ÉVALUATION DE LA RÉMISSION DANS LA DÉPRESSION

Le critère de rémission a progressivement remplacé celui de réponse thérapeutique dans l’évaluation de l’efficacité des traitements antidépresseurs. C’est en effet ce critère qui est désormais le gold standard dans les essais contrôlés au long cours. On considère généralement qu’un patient est en rémission lorsque les critères diagnostiques de dépression ont disparu depuis plus de deux mois consécutifs. La persistance de symptômes résiduels dans les rémissions partielles représente un facteur de risque de rechute précoce puis de récidive. L’état de rémission partielle est lui-même hétérogène puisque l’espérance d’une récupération fonctionnelle complète est moindre lorsque persistent plusieurs symptômes, même d’intensité légère. Les meilleurs critères d’une rémission de haute qualité sont la disparition des critères diagnostiques durant au moins deux mois, une note de 1 à la CGI-amélioration, une note nulle ou au maximum égale à 3 à l’échelle de dépression de Hamilton et un retour à l’état de fonctionnement général prémorbide. L’évaluation fine d’une symptomatologie résiduelle éventuelle permet de retenir la stratégie thérapeutique paraissant a priori la plus adaptée pour obtenir une rémission complète des troubles.